The report said the published literature provided by drug companies to justify their FDCs were not relevant and relied on a few biased studies

The subcommittee of Drug Technical Advisory Board (DTAB), which recommended a ban on 343 fixed dose combination (FDC) drugs and restricted another six, said most companies failed to generate safety and efficacy data to justify their FDCs.

The report said the published literature provided by companies to justify their FDCs were not relevant and relied on a few biased studies.

Even the indications mentioned were too vague, sometimes outrightly absurd and were not as per the treatment guidelines.

An FDC is a cocktail of two or more active drug ingredients in a medicine.

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Moneycontrol accessed a copy of the subcommittee report that ran into 693 pages.

The government based on the subcommittee report last week banned 329 FDC drugs citing lack of therapeutic justification. Another 15 (mostly) cold and cough brands managed to escape the ban as the court felt they had been in existence before 1988.

The subcommittee pointed out that use of banned FDCs would lead to unnecessary overuse and patients would be exposed to the risk of multiple ingredients when one would suffice. It raised the red flag on dosing mismatch among ingredients and warned about toxicity or lack of effect.

The six-member sub-committee chaired by Nilima Kshirsagar, National Chair Clinical Pharmacology, Indian Council of Medical Research (ICMR) - Mumbai, was formed in February to relook banned FDCs and give its recommendation.

It sought the help of 35 medical experts from across the country. It met 41 times, of which 39 meetings were held to review the information submitted by appellants and to provide a hearing and finalise its recommendation and report.

The subcommittee considered risk, therapeutic value and therapeutic justification for ingredients of the FDC as per Central Drugs Standard Control Organisation (CDSCO) and World Health Organisation (WHO) guidelines.

It received 812 representations related to 184 FDCs and heard 467 companies for 156 FDCs. The panel publicly available literature in scientific peer reviewed journals and standard treatment guidelines by national, international (followed in India) organisations and WHO.

Some of the observations made by the subcommittee are:

Quality of information

It observed that most companies had not generated efficacy or safety data for their own FDCs. “They could not provide any supportive data for the combination from literature. Also, the evidence provided was not relevant to the FDC under consideration,” the report said.

Several published studies provided in support of the FDCs were poorly designed or their full-texts were not made available and were at times in foreign languages (without translation), it stated.

One of the company to support its FDC provided evidence from a study done on infants and primary school children related to mixed infection causing diarrhea in Zakho city, Kurdistan Region of Iraq. The subcommittee commented that the data is not relavant to Indian context.

In another instance a pharma company submitted any entire material supporting its FDC in Russian. Some have just submitted abstracts of the studies, while others submitted material that's not relevant to the FDC in question.

Safety

According to the report, companies informed the subcommittee that FDCs was being marketed in the country for several years and there have been no reports of adverse reactions from prescribers or consumers. Prescribers were generally happy with FDCs and annual sales were good, the companies claimed.

The subcommittee disagreed with this assertion, saying that the absence of information regarding adverse events cannot be equated with absence of adverse events/side-effects.

“Authentic information about adverse effects can be generated through active surveillance. Given the absence of active pharmcovigilance system in place, it is difficult to equate lack of reports with actual safety of an FDC,” the subcommittee said.

Indications

The subcommittee found that the information provided regarding indications was at times unclear and included disorders which were not concerned with the FDC. It noted that appellants were not able to state the approved indications for the FDC they were manufacturing or marketing.

“Appellants requested the subcommittee to allow them to change the indications during the presentation, probably unaware that addition and/or change of indications requires processing of application as a new drug,” the report said.

Ingredients

The report flagged several FDCs having constituents that were required to be given at different frequencies during the day. For instance, in one particular combination involving Salbutamol, Cetrizine and Ambroxol, Cetrizine has to be consumed once a day while Sabutamol is prescribed 3-4 times a day. So, in this case a user will be consuming Cetrizine beyond the prescribed level.

In some FDCs, the constituents were found irrelevant to the indication stated. Take the case of Cetrizine, Dihydrochloride and Diethyl Carbamazine FDC. The indication was mentioned as 'Tropical Pulmonary Eosinophilia and Asthma'. Neither of the drugs has any role in the management of asthma. Moreover, Cetrizine has no role in the management of tropical pulmonary eosinophilia.

OTC productsThe report said some companies have claimed safety by quoting FDCs sold as OTC products in the UK or US. The subcommittee said these claims ignored the lacunae in the over-the-counter system, didn't follow label requirements for OTC products, lack efficacy and have been withdrawn by the innovator in some cases. Also, the panel pointed out that the OTC products in US and India are not comparable as they use different ingredients.